Childhood bronchiectasis: national incidence, disease progression and an evaluation of inhaled antibiotic therapy

Abstract

Background: Bronchiectasis is a chronic suppurative lung disease, defined by dilatation of bronchial airways, resulting in significant morbidity, mortality, and healthcare expenditure. It continues to affect large numbers of people worldwide, particularly indigenous or disadvantaged communities. The goals of this thesis were to determine childhood bronchiectasis occurrence in New Zealand, define its progression, and evaluate a potential new therapy; inhaled antibiotics. Methods: Firstly, a single-centre retrospective study described the prevalence, aetiology and severity of childhood bronchiectasis in Auckland. Secondly, a two year prospective multi-centre study described the incidence, aetiology and severity of new cases of bronchiectasis in New Zealand. Thirdly, disease progression was estimated through retrospective linear mixed-model analyses of pulmonary function and compared to peers with cystic fibrosis. Fourthly, an evaluation of inhaled gentamicin pharmacokinetics was made through a single-dose open-label study. Finally, a randomised double-blinded placebo-controlled two-period community-based crossover trial of inhaled antibiotics was conducted. Results: Children identified had severe, extensive bronchiectasis with an Auckland prevalence of 1:3000 and a national incidence of 3.7:100,000 per year. Compared with New Zealand children of European ethnicity, the incidence was 12 times higher in Pasifika and 3 times higher in Maori. Pneumonia, poverty, immunodeficiency, aspiration and recent immunosuppressive therapy were the most important aetiologies. Children with bronchiectasis had more severe obstructive lung disease than peers with cystic fibrosis (FEV1 intercept at ten years age 63% versus 77% predicted, p<0.001) but declined more slowly (-0.9% versus -2.5% predicted per annum, p=0.02). Inhaled gentamicin (80mg) safely achieved target concentrations within sputum (mean 697 μg/g). Despite low adherence, inhaled gentamicin was well tolerated, resulted in reduced symptoms, decreased Haemophilus influenzae density (-2.7 log10 cfu/ml, p<0.001), decreased airway inflammation (neutrophils, IL-1β, IL-8, TNFα) and reduced oral antibiotic use (OR 0.19, p<0.001). No significant change in spirometry or hospitalisation rates occurred over the three months. Conclusion: Childhood bronchiectasis has a high and increasing prevalence in New Zealand, especially in Pasifika and Maori. Children have extensive, progressive disease despite ‘standard’ management. Inhaled gentamicin is well tolerated, achieves effective concentrations, improves symptoms, reduces bacterial load and airway inflammation aswell as oral antibiotic use. However, low adherence suggests poor acceptability.